The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL/6J mice. This work reports a RIPK1 degrader that serves as a chemical probe for investigating the scaffolding functions of RIPK1 and as a potential therapeutic agent to enhance tumor responses to ICBs therapy.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1038/s41467-024-55006-2 | DOI Listing |
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649918 | PMC |
Publication Analysis
Top Keywords
Similar Publications
Development of a RIPK1 degrader to enhance antitumor immunity.
Nat Commun
December 2024
The Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.
The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo.
View Article and Find Full Text PDFEmamectin benzoate and nanoplastics induce PANoptosis of common carp (Cyprinus carpio) gill through MAPK pathway.
Pestic Biochem Physiol
December 2024
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural, Harbin, 150030, China. Electronic address:
Emamectin benzoate (EMB) is a pesticide that is frequently used. Nanoplastics (NPs) are a recently identified class of pollutants that are ubiquitous in the environment. In the aquatic environment, NPs can appear together with EMB, which may exacerbates the damage to water and aquatic organisms.
View Article and Find Full Text PDFAnti-inflammatory and cytoprotective polypharmacology of Canephron N reveals targeting of the IKK-NF-κB and p38-MK2-RIPK1 axes.
Biomed Pharmacother
December 2024
Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria; Department of Pediatrics I, Medical University of Innsbruck, Innsbruck 6020, Austria. Electronic address:
Urinary tract infections are among the most frequently occurring forms of infection, and inflammation and tissue damage contribute significantly to symptoms, e.g., dysuria and urge.
View Article and Find Full Text PDFMechanisms of H2pmen-Induced cell death: Necroptosis and apoptosis in MDA cells, necrosis in MCF7 cells.
Heliyon
December 2024
Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
Breast cancer is the second leading cause of cancer-related deaths in women around the world. Several cancer therapeutics have already been discovered and are being used to treat breast cancer. However, most of them cause severe side effects.
View Article and Find Full Text PDFSerum Level of RIPK1/3 Correlated With the Prognosis in ICU Patients With Acute Ischemic Stroke.
Immun Inflamm Dis
December 2024
Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Background: Acute ischemic stroke (AIS) is a common cerebrovascular disease with high mortality. AIS patients in the intensive care unit (ICU) often have severe conditions that require close monitoring and timely treatment. Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 play important roles in cell apoptosis and inflammation.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!